DMAP Pharmaceuticals and Agrochemicals Product Brochure...DMAP Pharmaceuticals and Agrochemicals...

DMAP Pharmaceuticals and Agrochemicals

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Introduction Page 1

Properties 2

a) Physical 2b) Toxicological 2c) Handling 3d) Shipping 3e) Specifications 3

Chemistry 4

Acylation 4a) Hydroxyl groups 4b) Amine groups 11

Alkylation 14a) Hydroxyl groups 14b) Amine groups 16c) Silylation 16d) Phosphorylation 17

Esterification 18

Halogenation 19

Enolates 20

Isomerization 21

Sulphonylation 21

Carbamoylation 21

Heterocyclic chemistry 22a) Cyanuric acids 22b) Penicillins 22c) Pyrrolidones 22d) Solid phase synthesis 23e) Cyanation of thiols 23f) Rearrangements 24g) Vilsmeier Amidation 24h) Bischler-Napieralski cyclization 25i) Dehydration 25j) Baylis-Hillman reaction 25

Polymer chemistry 26

Polyurethanes 26

Polyamides 26

Polyesters 26

Polycarbonates 26

Polyacrylates 27

TACT polymers 27

Example of Preparations 28

References 29

Contents

The protection of various functionalities with acetate and tosylates, (and similar groups such as mesylates, benzoates, tritylates, etc.) is well-known. In fact, treatment of amines and alcohols with acetic anhydride in the presence of a base, such as pyridine, has been a well-established procedure since the turn of the 20th century.

An example of this can be seen when reading the old carbohydrate literature. Often, to obtain solid, crystalline derivatives of sugars and glycosides, the product was peracetylated using this methodology. This allowed comparison to known authentic compounds that were also peracetylated. In early days these comparisons were not spectral, but were by melting point and mixed melting point.

This derivitization procedure generally works well, except on sterically hindered substrates, or where the substrate is electronically deactivated.

It was not until the late 1960s that certain dialkylaminopyridine catalysts were discovered to be useful as more difficult acylations. One of these catalysts was 4- (N,N-Dimethylamino) pyridine, DMAP (1)1.

Generally DMAP enhances the rate of acylation by a factor of approximately 10,000.

There is a good review of the literature2, covering the period prior to 1968. Since that time many industrial applications have been developed for DMAP. In fact, since the review, further work has demonstrated that DMAP has many applications outside of the acylation catalysis field.

Since the resonance interaction of the electron-donating 4- (N,N-Dimethylamino)- function on the pyridine ring greatly activates the ring nitrogen toward nucleophilic substitution, DMAP is an exceptional catalyst for a host of electrophilic substitution reactions. It is a well known acylation catalyst, but it also enhances the yield, conversion and rates of many other reactions.

DMAP can also enhance formylation, carbamoylation, benzoylation, tritylation, silylation, esterification, phosphorylation, polymerization of amides, esters, urethanes and many other reactions.

DMAP finds uses in the synthesis of many pharmaceuticals, agrochemicals and general fine chemicals as well as in the flavor and fragrance, photographic, cosmetic and polymer industries.

Introduction

(1)

1

Properties

2

a) Physical

DMAP, cas no. [1122-58-3], is registered on the following inventories:EINECS :2143535TSCA :ListedIts molecular formula is C7H10N2, with a corresponding molecular weight of 122.17. It is a colorless, crystalline solid with a melting point of around 112oC, and a boiling point of ca 160oC at 50mmHg. The solubility in water is 7.6g/100ml, (7.6% w/v) at 25oC, and it is soluble in solvents such as alkanes, chloroalkanes, aromatics, amines, alcohols and esters – some of which are often used as solvents in reactions where DMAP is employed.

b) Toxicological

• Toxic by all routes. • Corrosive to eyes, skin and respiratory system. • May cause permanent damage.R-Phrases • R 23/24/25 Toxic by inhalation, in contact with skin, and if swallowed. • R 34 Causes burnsS-Phrases • S 7/8 Keep container tightly closed and dry. • S 9 Keep container in a well ventilated place. • S 22 Do not breathe dust. • S 26 In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. • S 36/37/39 Wear suitable protective clothing, gloves and eye/face protection. • S 45 In case of accident or if you feel unwell, seek medical advice immediately (show label where possible).

Some data that are available are shown below:

Test type LD50 (mg/kg)Oral (rat) 230Oral (rat) 140Oral (rat) 95Oral (mouse) 119Dermal (rat) 500aDermal (rat) 50bDermal (rabbit) 90cDermal (rabbit) 90a: 5% w/v aqueous solutionb: 12.5% w/v aqueous emulsionc: Pure material

There is no evidence of carcinogenic properties, nor is there evidence of mutagenic effects, (Ames test – negative), or teratogenic effects.

3

c) Handling/Spillage • Wear suitable protective clothing, gloves and eye/face protection.• Do not scatter spilled material with high-pressure water streams.• Dyke fire control water for later disposal.

Thermal decomposition will lead to release of toxic fumes of hydrogen cyanide, as well as oxides of nitrogen and carbon. Primary extinguishing media should be water spray, fog or regular foam.

d) Shipping

Classification Toxic Solid, Corrosive, Organic, N.O.S.Class 6.1UN Number 2928Packing Group IISecondary Hazard 8

e) Specifications

TEST UNITS DMAP TECH DMAP FLAKE/PRILLSAppearance N/A Light to dark tan powder White to slightly off-white flakes/ prills, free from visible contamination

Identity (IR) N/A Compares to reference spectrum Compares to reference spectrum

Melt point °C 111.0 – 113.0 111.1 – 113.0

Water content % w/w Maximum 0.5 Maximum 0.10

Assay % w/w 99.0 – 101.0 99.0 – 101.0

Solvent % w/w Maximum 0.5 Maximum 0.10

GLC % area ••••••••••••••••••••••••••• Minimum 99.0

Color/Clarity PT/Co ••••••••••••••••••••••••••• Maximum 30, Clear Solution

Chemistry

4

Acylation

a) Hydroxyl groups

One of the first observations that DMAP was a useful catalyst in the acetylation of sterically hindered tertiary alcohols was seen in the acetylation of 1-Methylcyclohexan-1-ol1.

Under standard acetylation conditions with acetic anhydride-pyridine at ambient temperature overnight, the acetate product (2), was only formed in 5% yield.

However, when treated with a catalytic amount of DMAP and triethylamine as base, under comparable conditions, the yield was raised to 86%. Although not optimised, using as little as 5% w/w of DMAP to substrate can often effect the transformation to a satisfactory extent. In some cases, where the acylation is somewhat trickier, heat is required to enhance reaction rates.

Another good example is seen when observing the acetylation of hydroquinone. It is known that attempted mono acetylation of hydroquinone often results in mixtures of mono- and bis-acylated products, as well as unreacted starting material. Johnston3 found that even using a protection strategy of benzylation, or benzoylation of one of the OH groups, followed by acetylation and then deprotection, only afforded the mono-acetate in 40-45% yield.

5

Upon the addition of 0.05% w/w of DMAP, the mono acetate was formed in 65% yield in 15-30 minutes, without the need for additional protection-deprotection steps.

It should be noted that: • Generally a DMAP to substrate ratio of 1:20 is sufficient. • Generally a non nucleophilic base such as pyridine or TEA should be used in stoichiometric amounts (with respect to substrate), to remove the acid produced. • Generally anhydrides are superior to acid chlorides in this procedure.

Many solvents have been used, including pyridine, toluene, hexane, ethyl acetate and chlorinated solvents.

Industrial uses of DMAP in acylation are many and varied. For instance, in the synthesis of Pravastatin, a typical example of the acylation step shown below uses DMAP:

Here, pyridine is the base and the DMAP is used in approximately 6% w/w. Even after chromatography, the recovered yield was 89% of the acylated product.

6

Another “statin” or antihyperlipademic, which uses DMAP in the synthesis for the same acylation, is Simvastatin4. In the example below 2,2-Dimethylbutyryl chloride is used rather than the anhydride shown in the Pravastatin synthesis.

In fact, if the synthesis is carried out using the chiral acid chloride, then the product could actually be Lovastatin, which has the optically active ester grouping on the naphthol functionality.

Likewise, in the synthesis of Montelukast5 (3), acylation is a key step in the synthesis; in this case it is the preparation of themono-benzoylated cyclopropane derivative (4).

Note that the reduction can be done without using lithium aluminium hydride, but the more user-friendly VitrideTM (also supplied by Vertellus), as well as Pyridine (another of Vertellus products).

7

Even more complex molecules such as Paclitaxel, Taxotere and Docetaxel require simple acylation and/or protection. For instance in Docetaxel, DMAP is used not only in the acylation of the oxazolidinone (5), but also in the synthesis of the “BOC” protected amine (6).

DMAP is also used later in the synthesis when the coupling of the side chain made from (6), by reaction with 2-acetoxypropene to form the chiral oxazolidine carboxylic acid, is coupled to the “macrocycle” – the process essentially being an esterification, although may proceed through a mixed anhydride or using a mild reagent such as oxalyl chloride to retainconfiguration when making the acid chloride.

It is also well-known that antiviral drug synthesis benefits from the use of acylation catalysts such as DMAP.

8

Yet another case of acetylation, the more common acylation, is that of the Progestogen Ethynodiol diacetate6 (9). This is made by acetylation of Ethynodiol using DMAP as catalyst:

Consider the case of Hevizos, (7). A relatively simple molecule, assembled from a typical pyrimidinedione and a substituted furanose. The furanose, actually 2-Deoxy-D-ribofuranose, is converted to the alpha-methyl ether on the anomeric carbon center and then the remaining secondary and primary hydroxyl functions are protected with p-toluene sulphonyl chloride to afford (8), to allow functionalization of the anomeric hydroxyl function to prepare for coupling to the pyrimidinedione:

9

There are also many examples of acylation in antiviral drugs such as Famciclovir7 (10):

A range of derivatives of Raloxifene have also been investigated for treatment of osteoporosis. These derivatives were made using DMAP catalysis:

10

These examples illustrate the usefulness of DMAP in industrial applications. There are many other examples where DMAP can be of use, particularly in the acylation of hindered phenols. For example, DMAP has been used in the formylation of sterically hindered phenols which either fail to react in conventional Reimer-Tiemann, Gattermann and Duff reactions, or afford low yields. In the example shown, the benzaldehyde is formed in high yield9, using only 4 mol% DMAP in the acylation step.

In the antiobesity drug, Orlistat8, the acylation step using N-formyl-L-leucine also benefits from the use of DMAP; yields of 98% in 18 hours have been noted:

11

High regioselectivity can also be achieved using DMAP as catalyst, again in small loadings:

Here, the O-Acetylation is via the enolate.

b) Amine groups

There have been studies performed on the DMAP catalyzed acylation of amines, one of which illustrates the effectiveness in comparison with other bases18. The benzoylation of 3-chloroaniline shows the immense benefit of using DMAP as a catalyst:

Catalyst Relative rate

3-Cyanopyridine 14

Pyridine 568

2-Methyl pyridine 29



4-Phenoxy pyridine 4800

2,6-Dimethyl pyridine 8

DMAP 3140000

Quinoline 138

Isoquinoline 2620

N,N – Dimethylaniline (DMA) 29

Quinuclidine 185000

Trimethylamine 967

Relative rate = rate of catalyzed reaction rate of uncatalyzed reaction

Note the DMAP is almost 17 times better than Quinuclidine, and more than 10,000 times more effective than normal bases used in this type of reaction, such as DMA and TEA.

12

Also, in the synthesis of Glimepiride11 (13), the protection of the trans-4-amino-1-methylcyclohexane, acylation is used, to afford the intermediate (14):

Apart from the “BOC” protection shown earlier, Nitrogen as well as Oxygen functionality can be acylated. In the synthesis of the antihypertensive Ramipril10, (11), a key intermediate of which is Methyl-(S)-2-acetamido-3-chloroproprionate, (12):

13

In the treatment of hypercholerterolemia, Ezetimibe12 (15), drug which when DMAP is applied in the synthetic pathway, to make the key intermediate (16).

14

The alkylation of (17), when done under standard conditions with just the glycoside and trityl chloride in pyridine, afforded 39% yield at ambient temperature, and at up to 100C, only afforded 61% after 1 hour, along with 10% of a bis-tritylated byproduct. The same transformation using DMAP in DMF as solvent at ambient temperature afforded the product in 88% yield, uncontaminated by the bis-ether. The formation of the N-tritylated DMAP, (19), is postulated as the active alkylating agent.

Alkylation

a) Hydroxyl groups

Protection of hydroxyl functions using benzoylation and tritylation is often used in organic synthesis. Before looking at examples, it is worth noting that the alkylation agent is in fact the salt of DMAP.

Consider the case of tritylation of alpha-methylglucopyranose (17), to its protected ether at the primary hydroxyl function, (18).

15

Examples of alkylation can be seen when looking at the synthesis of antivirals such as Ganciclovir13, (20), the key stephere being the acylation of the amine, a protection required during synthesis:

Similarly, Famciclovir14 (21), Valciclovir15 (22), and other antivirals benefit by the use of DMAP. In both these cases, also for the acylation in the penultimate step.

16

c) Silylation The use of DMAP provides a satisfactory method for selective silylation of primary alcohols, often avoiding formation of byproducts formed by silylation of other hydroxyl groups such as secondary alcohols. This can be seen in most areas where sugars are employed. A good example of this can be seen when examining the silylation of glycols:

b) Amine goups DMAP can also have a beneficial effect on alkylation of amines in the synthesis of the platelet antiaggregant, Clopidrogrel16 (23).

If DMAP is used (4 mol%) in the presence of TEA at ambient temperature for 8 hours, 95% of the primary silyl ether is obtained, along with only 5% of the di-silyl compound and none of the secondary ether. Compare this to conditions where normal silylation reagents are employed, such as imidazole, and the ratios become less specific with 59% of the desired primary ether, along with 11% of the secondary and 30% of the bis-silyl ether.

Silylation reactions involving DMAP have also been used in guanosine19, Uridine20, and various nucleoside analogues as well as natural product synthesis. Phosphoenolpyruvate, which plays an important role in ATP biosynthesis, can also be prepared through a silyl ester intermediate, the formation of which requires DMAP21. Silyl esters, intermediate in the synthesis of the polyether divalent cationophore antibiotic calcimycin22, the antibiotic aphidicolin23, and the diterpene, trihydroxydecipiadiene24, all employ DMAP as the catalyst.

17

One surprising point to note is that when an attempt was made to prepare N-silylated amines, (24), by reacting secondary amines in DMF with TBDMSCl in the presence of TEA as base and DMAP as catalyst, the N-Formylated amines, (25), were produced instead.

d) Phosphorylation Really a simple alkylation procedure, DMAP has been used to catalyze phosphorylation of alcohols in the synthesis of Chloropyriphos17 (26).

18

Esterification A typical example of a simple esterification is that of linalool, which is converted to linalyl acetate with acetic anhydride and DMAP:

Shikimic acid (27), plays an important role in the biochemistry of plants and micro organisms. In an investigation25 into the total synthesis of methyl shikimate and 3-phosphoshikimic acid, the intermediate phosphate (28), was synthesized using DMAP catalysis.

Likewise, (-)-Menthol undergoes facile reaction with phthalic anhydride in the presence of DMAP to give a high yield (92%), of the hemiphthalate.

19

There are many examples of esterification, including exhaustive methylation using DCC26-28. Esters29,30 and thioesters31 can be prepared in good to excellent yields by reaction of the appropriate acid and alcohol, (or thiol), with DCC and 3-10 mol% of DMAP.

In another example, when malonic acid was treated with t-butanol, only 29.5% yield was obtained without DMAP as catalyst, the yield of which rose to 85.5% upon addition of DMAP30. The presence of the DMAP suppresses unwanted side reactions such as anhydride formation.

An example that illustrates the usefulness of DMAP in suppressing anhydride formation is seen when alkyl chloroformates are used for the high-yield esterification of carboxylic acids32,33. The table below shows the effect of adding various amounts of DMAP to equimolar amounts of benzoic acid, ethyl chloroformate and TEA:

Halogenation A tosyl chloride/DMAP system34 has been shown to be an effective means of converting primary, 2,3-epoxy, allylic, propargylic and glycosdic alcohols to the corresponding chlorides. Aliphatic alcohols do not give the chlorides, they stop at the intermediate tosylate stage.

Product distribution

Equivalents of DMAP Ethyl benzoate Benzoic anhydride

0.01 56% 33%

0.10 82% 10%

0.50 91% <1%

20

Enolates Acylation of enolates sometimes also results in rearrangement. In the case of the cyclohexanedione herbicides such as Sulcotrione35, (29) and Mesotrione, (30).

The reaction also applies to bromination, and compounds such as 1-bromodecane have been synthesized in this manner.

Similarly in the synthesis of the selective herbicide Sethoxydim36, (31), the acylation proceeds with DMAP as catalyst.

21

Isomerization DMAP has been used successfully to isomerize Z- and E-dehydroamino acids when traditional bases, such as TEA, DABCO, DBU, failed37.

Sulphonylation DMAP functions effectively as a mesylation catalyst38, for example:

Carbamoylation A good example of how effective DMAP is in catalyzing this reaction is to be seen when investigating the carbamoylation of m-Cresol3.

Under the same conditions, but without DMAP added, the yield drops from quantitative to ZERO!

22

b) Penicillins Treating isocyanatopenicillinates with glycine derivatives gives ampicillin derivatives, a reaction which is greatly facilitated by DMAP39.

Heterocyclic chemistry DMAP catalyzes a whole range of inter- and intra-molecular cyclizations, most of which can be identified in the literature – our advice – “stick some in – give it a try.” The following are some examples that illustrate where DMAP can be utilized.

a) Cyanuric acids Aryl isocyanates, when treated with DMAP thermally trimerise, via the intermediate DMAP-carbamoyl salts3.

c) Pyrrolidones Glutamic acid undergoes cyclization when treated with acetic anhydride and DMAP in the presence of TEA40.

23

d) Solid phase Synthesis For those interested in solid phase synthesis, there is an excellent review by Brase41. This review covers benzoannelated heterocycles such as benzodiazepines and indoles, and shows how they can be prepared efficiently though cyclization on solid supports. Many of these preparations are equally applicable to the non-solid phase synthesis using traditional methods, but incorporating DMAP. In the review, a number of synthetic strategies are put forward, including classical heterocyclic ring formation reactions.

An example of this is the Fisher indole chemistry was peformed on the Rapp TentaGel resin, and then the cleavage was carried out to free the product from the resin.

e) Cyanation of thiols Reaction of DMAP to make stable salts has already been discussed. One of the salts is that of DMAP and cyanogen bromide. In this example, as the stable perchlorate salt.

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Another example illustrates how DMAP can alter the course of a reaction. In an article where phthalic anhydride was subjected to reaction with an ynamine in the presence and absence of DMAP, Steglich and Hofle42 recorded that without DMAP catalysis, only the minor product, (32) is formed.

f) Rearrangements There are many examples of rearrangements that occur better in the presence of DMAP. For instance, the rearrangement of acyloxyoxazoles apparently proceeds 10,000 times faster in the presence of DMAP:

g) Vilsmeier Amidation Chemists at Fujisawa experienced the usefulness of DMAP when they screened it in the synthesis of their target compound. In using standard bases such as N-methylmorpholine and triethylamine, they suffered from low yield, slow reaction and poor quality product. When using DMAP with TEA, the reaction was completed within 15 minutes, giving high quality product in excellent yield.

25

h) Bischler-Napieralski cyclization An example of intermolecular cyclization can be seen in this simple ester condensation.

i) Dehydration Even in relatively trivial reactions, DMAP can show positive benefits. For example, the dehydration of the tertiary alcohol to afford the alkene, proceeds at relatively low temperatures.

j) Baylis-Hillman reaction The hydroxymethylation of cyclohexenones can be catalyzed by DMAP:

Polymer chemistry

26

There is extensive literature preference for use of DMAP in polymer chemistry. It has been used in Polyurethanes, Polyphenylenes, Triazines, Polysiloxanes, Polyols, Fluoropolymers, Polyphosphoesters and many other systems.

Some typical examples of uses are given.

Polyurethanes

DMAP catalyzes the reaction of isocyanates with either alcohols or phenols to afford the polyurethanes. The mechanism of this reaction is thought to be one of base catalysis, rather than the more usual mode of action, which for DMAP is nucleophilic catalysis.

Polyamides


Polyesters


Polycarbonates


27

Polyacrylates

An example of a polyacrylate is seen in the optical lens polymers. Polymers and copolymers produced from aromatic based methacrylates, acrylates and dimethacrylates are excellent materials with a wide variety of uses such as dentistry and optical items. In typical examples, DMAP is employed to esterify the reactive hydroxyl functions of aromatic systems, (as we have seen earlier), used as monomers eg:

TACT polymers

Tris (alkoxycarbonylamino) triazine, or TACT has been successfully formulated with acrylic and polyester backbone resins in coating applications. TACT is a new form of melamine resin that is formaldehyde-free to comply with VOC and OSHA regulations.

Example of Preparation

28

Preparation of chlorpyrifos, i.e., O,O-diethyl O-(3,5,6-trichloro-2-pyridyl)phosphorothioate.

Into a 700 millilitres (ml) baffled reactor equipped with heating means, a mechanical stirrer made up of two sets of four blade turbines, a condenser, a dropping funnel, a thermometer and a pH probe, were placed 99.5 grams (g) (0.417 moles) of sodium 3,5,6-trichloro-2-pyridinate monohydrate, 400 ml of water 0.06 g (0.0005 mole) of 4-dimethylaminopyridine, 3.6 g (0.058 mole) of ortho boric acid, 24.1 g of NaCl, 3.5 g (0.0875 mole) NaOH and 0.5 g of polyglycol PG 26-2 surfactant. PG 26-2 surfactant is the product of reaction of di-sec-butyl phenol reacted with 5 moles of ethylene oxide add 4 moles of propylene oxide and has an HLB Value in the range of 8 to 10.

The reaction mixture was heated to a temperature of 45°C. while stirring at 1,000 rpm and 75.0 g (0.398 mole) of O,Odiethylphosphorochloridothioate was added during the course of 5 to 10 seconds. The reaction mixture was maintained at 45°C. and the vigorous stirring continued for 2 hours, during which time the pH dropped from an initial value of 12.3 to 10.15.

The chlorpyrifos product was recovered by filtering off unreacted sodium 3,5,6-trichloro-2-pyridinate and separating the organic and aqueous layers while the reaction mixture was still at about 45°C. The organic, or product, layer was immediately washed once with 60 ml of water and dried by vacuum stripping. The product was found to consist of 133.7 g containing 98.5% chlorpyrifos in which the impurity sulfotepp was present only to the extent of 0.14%. The overall yield based on the amount of O,O-diethylphosphorochloridothioate used was calculated to be 94.4%.

References

29

1. W Steglich and G Hoefle, Angew. Chem, Int, Ed. Engl. 8 981 (1969)2. L. M. Litvinenko and A. I. Kirichenko, Dokl. Akad. Nauk SSSR, Ser.Khim., 176, 97 (1967) Chem. Abstr., 68, 68325u3. D. Johnston, Chem. Ind (London) 24, 1000 (1982)4. EP 299656 (1989)5. US 5968876. US 2,843,6097. EP 182024 (1986)8. EP 129748 (1986)9. D. J. Zwanenburg and W. A. P. Reynen, Synthesis, 624 (1976)10. EP 79022 (1988)11. EP 31058 (1983)12. US 59688713. US 4355032 (1982)14. Austral tppl 84 31,973,15. EP 308065 (1989)16. EP 99802 (1985)17. US 5120846 (1992)18. A. I. Kirichenko, L. M. Litvinenko, I. N. Dotsenko, N. G. Kotenko, E. Nikkel’sen and V. D. Berestetskaya Dokl, Akademii Nauk SSSR, 244, 1125 (1979) Chem. Abstr., 90, 157601c (1979)19. T. Hata et al,. Tetrahedron Lett, 21, 3899 (1980)20. L. Saito et al., Tetrahedron Lett. 25, 3325 (1984)21. T. Hata et al., Tetrahedron Lett. 22, 371 (1980)22. P.A. Grieco et al., Heterocycles 12, 1623 (1979)23. E.J. Corey et al., J. Am. Chem.Soc 102,1742 (1980)24. M L Greenlee, J. Am. Chem. Soc 103, 2425 (1981)25. P Nicolet and C. Laurence, J. Chim. Phys. Phys. – Chim. Biol 80, 677 (1983)26. B. Neises and W. Steglich, Angew. Chem. Int. Ed. Engl., 17, 522 (1978)27. A. Hassner and V Alexanian, Tetrahedron Lett., 4475 (1978)28. F. E. Ziegler and G. D. Berger, Synth. Comm., 539 (1979)29. A Hassner and V Alexanian, Tetrahedron Lett, 4475 (1978)30. B Neises and W Steglich, Angew. Chem. Int. Ed Engl. 17, 522 (1978)31. S Kim and S Yang, Chem Lett., 133 (1981).32. S Kim et al., Tetrahedron Lett. 24 3365 (1983)33. S Kim et al., J. Org Chem, 50, 560 (1985)34. K C Nicolaou et al., Tetrahedron Lett. 25, 2295 (1984)35. EP 137963 (1985)36. JP 81 75,408 (1996)37. C H Stammer et al., J. Org.Chem. 46 2667 (1981)38. M Ikeda et al., J. Org Chem. 48, 4241 (1983)39. Koninklijke Nederlandsche Gist – en Spiritusfabriek,N. V. , Ger. Offen., 2, 155, 152 (1972), Chem. Abstr., 77, 88491J (1972).40. J. Lepschy, G. Hoefle, L. Wilschowitz, and W. Steglich, Annalen, 1753 (1974).41. Brasse42. Steglich and Hofle Chem. Ber, 105, 1368, (1972)

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DMAP Pharmaceuticals and Agrochemicals Product Brochure...DMAP Pharmaceuticals and Agrochemicals...

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